A new mouse model of human tau pathology has been developed, by expression of the normal human tau gene in the absence of mouse tau (hTau mice). These mice show accumulation of phosphorylated tau in the somatodendritic compartment, a clear age-related increase in tau phosphorylation, conformational changes in tau and the formation of filamentous tau aggregates in neocortical, hippocampal and other neurons. There is evidence of astrocytosis, microgliosis and neuronal death in mice aged over a year. Our first goal will be to complete the detailed characterization of the tau pathology that develops in the hTau mice, over the entire life span. These studies will include quantitation of neuronal and synaptic density in neocortex and hippocampus, and examination of astrocytic and microglial reactions. The functional consequences of the development of tau pathology for cholinergic neurotransmission will be examined. The hypothesis that tau isoform ratios are the critical determinant of tau pathology and cell death will be tested by breeding hTau mice with mice expressing single isoforms of human tau as transgenes. In the course of development of hTau mice with different ratios of 3R and 4R tau, mice transgenic for 3R and 4R single isoforms on a null background will be generated, and these mice will be examined for the development of tau pathology. The possible role of a new gene, saitohin, discovered to reside within an intron of the human tau gene, will be examined by single and double label immunocytochemistry, and by biochemical techniques. The hypothetical roles of GSK3beta, cdk5 and other protein kinases in the formation of hyperphosphorylated tau aggregates will be examined using biochemical, pharmacological and genetic strategies. Finally, if neuronal death is confirmed to occur in the hTau mice, potential mechanisms will be explored, with special attention paid to the possibility that apoptosis is involved. [unreadable] [unreadable]